GLP-2 is a 33 amino acid product of the proglucagon gene. Recent evidence indicates that GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal mobility. Many of these effects have been attributed not only to the wild type peptide, but also to analogs thereof, including particularly those rendered resistant to digestion by serum-borne enzymes, such as DPP-IV, by substitution of the alanine resident at position 2 with, for instance, glycine. A variety of bioactive GLP-2 analogs are described, for instance, in U.S. Pat. No. 5,789,379.
With recent recognition of its pharmaceutical properties, there is a demand for large quantities of GLP-2 and analogs thereof to permit development and subsequent medical use of these products. Solid or solution phase synthetic methods have typically been applied to produce the research quantities of GLP-2 and analogs used to date. The production of GLP-2 as a recombinant product of genetically engineered hosts has been suggested, for instance in U.S. Pat. Nos. 5,789,379 and 6,287,806, and is described in U.S. Pat. No. 5,629,205. However, prior art production systems have limitations in terms of product yield and quality, and it would be desirable to provide a system that yields quality GLP-2 peptide in a cost-effective manner.
It is accordingly an object of the present invention to provide a process, and intermediates and reagents useful therein, by which commercial quantities of GLP-2 can be produced.
It is another object of the present invention to provide GLP-2 and analogs thereof, particularly the [Gly2]hGLP-2 analog, in structurally authentic form.